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Views of the NIH CLINICAL EPIDEMIOLOGY www.jasn.org Genetic Variants Associated with Circulating Fibroblast Growth Factor 23 Cassianne Robinson-Cohen ,1 Traci M. Bartz,2 Dongbing Lai,3 T. Alp Ikizler,1 Munro Peacock,4 Erik A. Imel,4 Erin D. Michos,5 Tatiana M. Foroud,3 Kristina Akesson,6,7 Kent D. Taylor,8 Linnea Malmgren,6,7 Kunihiro Matsushita,5,9,10 Maria Nethander,11 Joel Eriksson,12 Claes Ohlsson,12 Daniel Mellström,12 Myles Wolf,13 Osten Ljunggren,14 Fiona McGuigan,6,7 Jerome I. Rotter,8 Magnus Karlsson,6,7 Michael J. Econs,3,4 Joachim H. Ix,15,16 Pamela L. Lutsey,17 Bruce M. Psaty,18,19 Ian H. de Boer ,20 and Bryan R. Kestenbaum 20 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely under- stood; genetic variation may help explain interindividual differences. Methods We performed a meta-analysis of genome-wide association studies of circulating FGF23 con- centrations among 16,624 participants of European ancestry from seven cohort studies, excluding par- ticipants with eGFR,30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log–transformed FGF23 concentra- tion, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. Results We discovered 154 SNPs from five independent regions associated with FGF23 concentration. 2 The SNP with the strongest association, rs17216707 (P=3.0310 24), lies upstream of CYP24A1,which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each addi- tional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. Conclusions Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations. J Am Soc Nephrol 29: 2583–2592, 2018. doi: https://doi.org/10.1681/ASN.2018020192 Fibroblast growth factor 23 (FGF23) is secreted Received February 20, 2018. Accepted August 6, 2018. from bone and plays a role in both phosphate ho- meostasis and the vitamin D endocrine system. Published online ahead of print. Publication date available at www.jasn.org. FGF23 induces urinary phosphate excretion by suppressing the expression of the sodium phos- Correspondence: Dr. Cassianne Robinson-Cohen, Division of Nephrology, Department of Medicine, Vanderbilt University phate cotransporter in kidney proximal tubular Medical Center, Nashville, TN 37232. Email: cassianne.robinson- cells. FGF23 also suppresses the synthesis of calci- [email protected] triol [1,25(OH)2D] by inhibiting its production via Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: 2583–2592, 2018 ISSN : 1046-6673/2910-2583 2583 CLINICAL EPIDEMIOLOGY www.jasn.org 1,25a-hydroxylase (CYP27B1) and stimulating its degrada- Significance Statement tion via 1,24,25-hydroxylase (CYP24A1).1,2 In turn, calcitriol directly enhances the transcription of FGF23 to complete a Fibroblast growth factor 23 (FGF23), a bone-derived hormone that feedback loop. The effects of FGF23 on phosphate and vitamin regulates phosphorus and vitamin D metabolism, contributes to D homeostasis require klotho as an obligatory coligand, which the pathogenesis of mineral and bone disorders in CKD and is an fi emerging cardiovascular risk factor. The authors performed a meta- activates broblast growth factor receptors and their down- analysis of genome-wide association studies of circulating FGF23 stream signaling molecules.3 Optimal phosphate balance is concentrations among 16,624 individuals of European ancestry important for many physiologic functions, from cell signaling from seven cohort studies. Afteradjusting for age,sex, studysite,and to energy metabolism and skeletal mineralization. In humans, principal components of ancestry, they found that common genetic high FGF23 concentrations contribute to the pathogenesis of variants are associated with differences in circulating FGF23 con- centration; several are closely linked with enzymes, transporters, and mineral and bone disorders in CKD and are associated with receptors known to be critical to vitamin D metabolism and regula- ventricular hypertrophy, cardiovascular events, and prema- tion of phosphate levels. Future study of such variants may help ture death.4–12 illuminate the mechanism and clinical implications of FGF23’s role in Despite intense investigation, central elements of FGF23 reg- vitamin D and phosphate homeostasis. ulation remain unknown. The primary role of FGF23 in phos- phate homeostasis suggests regulation by serum phosphate excluded participants with eGFR,30 ml/min per 1.73 m2. concentrations; however, experimental studies have not detected This exclusion was chosen because our intent was to study direct actions of serum phosphate on FGF23. Rare heritable FGF23 under normal conditions, because the strong influence disorders are characterized by dysregulated FGF23 metabolism, of kidney disease may overwhelm potentially more subtle in- yet only two (autosomal dominant hypophosphatemic rickets fluences of individual SNPs on circulating FGF23. The indi- and familial hyperphosphatemic tumoral calcinosis) involve di- vidual studies were approved by the local research ethics 13–15 rect mutation of the FGF23 gene. Mutations in other bone committees, and informed consent was obtained from all metabolism genes cause familial tumoral calcinosis (GALNT3, participants. klotho), X-linked phosphatemic rickets (PHEX), and autoso- mal recessive hypophosphatemic rickets (DMP1, FAM20C, Measurement of FGF23 ENPP1), that subsequently alter FGF23 metabolism through Circulating FGF23 concentrations were measured by ELISA mechanisms that are not completely understood.16–23 We (Kainos Laboratories, Inc., Tokyo, Japan), which detects the performed a meta-analysis of genome-wide association studies full-length, biologically intact FGF23 molecule via midmole- of circulating FGF23 concentrations among 16,624 individuals cule and distal epitopes, in the ARIC, Indiana Sisters, MrOS of European ancestry from seven cohort studies, and replicated GBG and Malmo, and MESA cohorts. In the CHS and OPRA in 4443 individuals of African ancestry from three cohorts, to cohorts, FGF23 was measured using a C-terminal ELISA kit investigate the role of common genetic variants on this (Immutopics, San Clemente, CA). hormone. Genotyping and Quality Control METHODS Genome-wide genotyping and imputation with reference to the 1000 Genomes Phase 3 genotypes were performed inde- Study Populations pendently in each cohort. Each cohort applied sample and Seven cohorts contributed to the meta-analysis, by providing SNP-based quality control measures for missingness, – study-specific genome-wide analyses of FGF23 concentra- minor allele frequency, and Hardy Weinberg equilibrium tions, for a total of 16,624 individuals of European ancestry (Supplemental Table 1). Poorly imputed SNPs were excluded 2, , fi (Table 1). Contributing studies included the Atherosclerosis if R 0.3 or proper-info was 0.4. Population strati cation and Risk in Communities Study (ARIC; number of individuals of relatedness were assessed using the ancestry principal compo- European ancestry, n=8594),24 the Indiana Sisters Study nents as previously described.31 All cohorts used EIGENSTRAT (n=1128),25 Osteoporotic Fractures in Men Study–Goteborg for principal components of ancestry computation. (MrOS GBG, n=937),26 the Multi-Ethnic Study of Atheroscle- rosis (MESA; number of individuals of European ancestry, Statistical Analyses n=2163),27 MrOS Malmo26 (n=894), the Osteoporosis Pro- Each SNP was tested for association with natural log– spective Risk Assessment Study (OPRA, n=920),28 and the transformed FGF23 using linear regression in two additive ge- Cardiovascular Health Study (CHS; number of individuals netic models.32 Model 1 was adjusted for age, sex, and the first of European ancestry, n=1988).29 Detailed information on ten principal components of ancestry. the study cohorts and methods is provided in Supplemental FGF23 concentrations are strongly associated with eGFR Table 1 and Table 1. and body mass index (BMI). To detect FGF23 loci indepen- We calculated the eGFR using the creatinine-based CKD dent of these pathways and to diminish associations with Epidemiology Collaboration equation equation,30 and effects modulated through these factors, model 2 added 2584 Journal of the American Society of Nephrology J Am Soc Nephrol 29: 2583–2592, 2018 www.jasn.org CLINICAL EPIDEMIOLOGY Table 1. Cohort and study participant (European descent) characteristics Characteristic ARIC CHS Indiana MESA MrOS GBG MrOS Malmo OPRA Individuals of European descent 8594 1988 1128 2163 937 894 920 Age, yr 57.1 (5.7) 78.0 (4.4) 36.4 (8.5) 62.6 (10.3) 72.3 (5.7) 73.2 (5.8) 75.2 (0.1) Men, n (%) 3962 (46.1) 754 (38.3) 0 (0) 1025 (47.3) 937 (100) 894 (100) 0 (0) BMI, kg/m2 27.3 (5.0) 26.6 (4.5) 26.3 (6.0) 27.7 (5.1) 27.5 (3.7) 27.5 (3.7) 26.2 (4.1) eGFR (CKD-EPI), ml/min per 1.73 m2 87.8 (13.2) 72.1 (17.7) 103.5 (7.4) 76.0 (17.1) 71.6 (19.3) 68.8 (19.3) 68.0 (12.6) FGF23, pg/ml (intact) 45.5 (17.3) — 39.4 (17.4) 41.9 (17.6) 46.2 (22.5) 55.9 (27.7) — FGF23, pg/ml (C-terminal) — 12.9 (21.3) ——— —8.3 (9.1) Data are mean (SD) or number (%), as appropriate.
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